Summary:
- Amgen is developing maridebart cafraglutide (MariTide), an investigational obesity therapy that blocks one metabolic pathway and activates another.
- This unique approach to targeting obesity is based on promising data from both preclinical and human genetic studies.
Obesity affects approximately a billion people worldwide, and often has complex, underlying causes. To help address this significant unmet need, Amgen is developing tailored therapeutics, including maridebart cafraglutide, also known as MariTide (formerly AMG 133), an investigational therapy for the treatment of obesity and related conditions.
MariTide emerged from Amgen’s deep knowledge of human disease biology and genetics. “MariTide exemplifies how Amgen converts deep genetic insights into bold therapeutic strategies,” said Jay Bradner, head of Research and Development at Amgen. “By inhibiting GIPR — a move informed by human genetics and validated in preclinical models — MariTide offers a distinctly innovative approach to addressing obesity, one of the most pressing public health challenges of our time.”
MariTide is an antibody-peptide conjugate. It has a monoclonal antibody backbone linked to two identical peptides. The antibody backbone antagonizes, or blocks, the glucose-dependent insulinotropic polypeptide receptor (GIPR). The two modified glucagon-like peptide-1 (GLP-1) analog peptides agonize, or activate, the GLP-1 receptor.
GIP and GLP-1 are incretin hormones secreted by the gut after eating. The hormones bind to their respective receptors to trigger insulin secretion, which helps lower blood glucose levels. GIP and GLP-1 also play a role in appetite regulation.
Both GLP-1R activation alone and activating GLP-1R and GIPR with obesity (with and without type 2 diabetes) has been associated with weight loss. This research has led to the development of medicines that target one or both of these pathways.
Amgen, however, has taken a different approach, blocking GIPR rather than activating it. This decision was based on promising preclinical research and insights from human genetics.
The Amgen team tested more than 150 different variations of antibody-peptide conjugate molecules before identifying the most promising candidate – an antibody linked to two peptides, which are small pieces of a protein. The antibody component of MariTide (in blue) inhibits GIPR and the two peptides (in purple) linked to the antibody activate the GLP-1 receptor.
The Case for Blocking GIPR
A research team led by Murielle Véniant-Ellison, scientific vice president of Research at Amgen, was doing preclinical investigations on the effects of blocking GIPR and activating GLP-1R. The team, based at Amgen’s Thousand Oaks, California, headquarters, saw that inhibiting GIPR in mice fed a high fat diet prevented the mice from gaining weight. Activating GLP-1R led to a decrease in body weight, which is a well-known effect. Blocking GIPR and activating GLP-1R in these mice also resulted in significant body weight reduction.
Murielle Véniant-Ellison, scientific vice president of Research at Amgen, has been researching metabolic disorders such as obesity and diabetes since she was hired in 2000.
When Véniant-Ellison and her team used molecules that targeted each receptor, separately, the mice lost weight, but when they combined the two molecules into one, the weight loss was greater. “That was a very exciting time to be able to see that,” said Véniant-Ellison, who has been at Amgen for over 20 years.
Amgen and others are still investigating the biology behind these pathways, and to better understand these findings, Véniant-Ellison turned to Amgen’s subsidiary, deCODE genetics, located in Reykjavík, Iceland. The group uses large-scale human genetic data to find variants that may influence health outcomes, including obesity.
The deCODE team’s research is focused on using population-scale resources to study human diversity. Over the years, this has led to the discovery of key sequence variants that may either protect against or increase the risk of a range of common diseases from cardiovascular disease to cancer.
With extensive access to human data from global populations, the genetic insights generated by the Reykjavík team are helping to shape the future of therapeutic development. For example, the team has flagged a number of interesting targets associated with obesity that were informed by human genetic observations.
In the case of MariTide, the Reykjavík research team and colleagues had searched for variants associated with lower body mass index in genetic data gathered from hundreds of thousands of individuals across biobanks from several countries. One of the variants they discovered was in GIPR.
When Véniant-Ellison’s team came to them, the scientists in Iceland did further analyses and determined that the variant disrupted the gene that makes GIPR, decreasing that gene’s activity. Lower GIPR activity was associated with lower weight in those people with that variant.
MariTide: An Innovative Approach
Together, these preclinical and human genetic discoveries helped lay the groundwork for MariTide. Positive Phase 2 study data have paved the way for a larger Phase 3 program. This research is just one example of how Amgen teams across the globe are dedicated to combining biological and human genetic insights to enhance innovation in drug design.
Learn more about our approach to treating obesity and related conditions: Amgen.com/obesity.